N-methyl-D-aspartate (NMDA) receptor antagonists relieve neuropathic pain in animal models, but side effects of dissociative anesthetic channel blockers, such as ketamine, have discouraged clinical application. Based on the hypothesis that low-affinity NMDA channel blockers might have a better therapeutic ratio, we carried out two randomized, double-blind, crossover trials comparing six weeks of oral dextromethorphan to placebo in two groups, made up of 14 patients with painful distal symmetrical diabetic neuropathy and 18 with postherpetic neuralgia. Thirteen patients with each diagnosis completed the comparison. Dosage was titrated in each patient to the highest level reached without disrupting normal activities; mean doses were 381 mg/day in diabetics and 439 mg/day in postherpetic neuralgia patients. In diabetic neuropathy, dextromethorphan decreased pain by a mean of 24% (95% CI: 6% to 42%, p = 0.01), relative to placebo. In postherpetic neuralgia, dextromethorphan did not reduce pain (95% CI: 10% decrease in pain to 14% increase in pain, p = 0.72). Five of 31 patients who took dextromethorphan dropped out due to sedation or ataxia during dose escalation, but the remaining patients all reached a reasonably well-tolerated maintenance dose. We conclude that dextromethorphan or other low-affinity NMDA channel blockers may have promise in the treatment of painful diabetic neuropathy.

The importance of N-methyl-D-aspartate (NMDA) receptor-mediated sensitization of central nervous system (CNS) neurons is well established in animal models of acute and chronic pain. A human model of central sensitization would be useful in screening new NMDA antagonists and establishing dose regimens for clinical trials in patients with pain related to sensitization of CNS neurons. We used this model to examine the effects of intravenous infusions of two centrally acting analgesics, the NMDA receptor antagonist ketamine and the morphine-like opioid agonist alfentanil. Twelve normal subjects completed a 3-session, randomized, double-blind, crossover study. From 25 to 60 min after capsaicin injection, subjects were given intravenous infusions of ketamine (mean dose: 32 mg), alfentanil (mean dose: 3075 micrograms), or saline placebo. Both drugs significantly reduced ongoing pain and pinprick-evoked hyperalgesia during the infusion. The reduction in allodynia evoked by light stroking was statistically significant only for alfentanil. Mean reduction +/- SEM relative to placebo were for ongoing pain: ketamine, 36 +/- 9%; alfentanil, 51 +/- 5%; area of pinprick hyperalgesia: ketamine, 34 +/- 7%; alfentanil, 35 +/- 7%; and area of mechanical allodynia: ketamine, 52 +/- 20%; alfentanil, 70 +/- 12%. Because the drugs were given systemically and produced side effects in all subjects, we cannot specify the site or sites of action nor conclusively rule out a non-specific 'active placebo' response as the cause for reduction of symptoms. Arguing against an 'active placebo' response, however, was the lack of analgesic effect of intravenous midazolam (mean dose; 3.4 mg, titrated to produce side effects of similar magnitude to ketamine and alfentanil) given at 145 min after capsaicin in 9 subjects who had received saline from 25 to 60 min. The results of this study suggest that neural systems sensitive to NMDA receptor antagonists and opioids participate in capsaicin-evoked pain phenomena, and support the feasibility of pharmacological studies using the intradermal capsaicin model.

Intradermal and topical application of capsaicin have been used to study mechanisms of mechanical allodynia (MA) and pinprick hyperalgesia (PPH) and the efficacy of drugs in relieving these symptoms. However, it is associated with significant inter- and intra-subject variability. In order to improve the model's sensitivity, we examined several potential sources of variability of capsaicin-evoked MA and PPH in healthy volunteers, including skin temperature fluctuations, method (intradermal vs. topical) and site (volar forearm vs. foot dorsum) of administration. In study I, 12 subjects received, in a 6-session, randomized, crossover trial, 1) 250 micrograms of intradermal (ID) CAP to the volar forearm with skin temperature fixed at 36 degrees C (36 ID). 2) 250 micrograms ID CAP with varying skin temperature (VT ID), or 3) 250 microliters of l% CAP patch placed on the skin at 36 degrees C. The resulting MA and PPH areas observed with each method were measured. In study II, a 4-session, randomized crossover trial, 12 subjects were given 100 micrograms ID CAP in the volar forearm or foot dorsum and subsequent areas of MA and PPH recorded. In study I, 5/12 subjects had small MA areas (< or = 5 cm2) and one subject had small PPH areas in at least 4/6 sessions. The most consistent intra-subject responses were seen with the 36 ID method. Correlation coefficients for the two sessions using the same method of administration were: MA; 36 ID r = 0.83, VT ID = 0.19. Topical r = 0.81; PPH: 36 ID r = 0.93; VT ID r = 0.38, Topical r = 0.78. In study II, 4/12 subjects had little MA for both forearm and foot though all subjects developed PPH. However, greater intra-subject consistency (MA: foot: r = 0.84; arm: r = 0.49; PPH: r = 0.87; r = 0.39) and significantly larger areas of MA (15.8 +/- 4.2 vs 9.1 +/- 2.5, p < 0.05) were seen with the foot. (PPH: foot: 28.9 +/- 6.7; arm: 21.6 +/- 4.2, NS). Large variability exists among subjects receiving CAP, with some developing minimal MA. However, these subjects may be screened out prior to entry, increasing the sensitivity of the model, which may be further improved by clamping the skin temperature.

Low cutaneous blood perfusion is related to the intensity of ongoing, spontaneous pain when secondary hyperalgesia is present. The specific trigger(s) have yet to be identified.